Using cerebellar granule cells as a model, we have found that long-term exposure to relatively high concentrations of carbazepine induces neurotoxicity, as evidenced by a loss of receptor-mediated phosphoinositide responses and 3H-ouabain binding to intact neurons. This neurotoxicity may be related to overdose effect of carbamazepine. NMDA fully reverses the neurotoxicity of carbamazepine and the protective effect is nullified by aminophosphovalerate. NMDA also protects neuronal death induced by glutamate. Long term exposure of cerebellar neurons to lithium induces biphasic biochemical effects. At clinically relevant concentrations, lithium is neurotoxic and causes neuronal death. In rats chronically treated with haloperidol, phosphoinositide turnover stimulated by dopamine and carbachol is significantly decreased in striatal and cortical slices. Chronic combined treatment with nicotine abolishes haloperidol's effect on phosphoinositide response in the cortex and hippocampus, but potentiates the same response in the striatum. In another study, it was found that neither lidocaine kindling nor repeated cocaine injection nor carbamazepine diet alters the ability of batachrotoxin to stimulate phosphoinositide hydrolysis in rat brain.